Lecture 2.2 - energy production (carbohydrate 3 and lipids).pdf

Catabolism of carbohydrates - stages 3-4: ◦Specifically related to mitochondria Catabolism of carbohydrates - end of stage 2: ◦Pyruvate is first converted to acetyl CoA by the enzyme pyruvate dehydrogenase (PDH) - regulated allosterically ◦The reaction is irreversible (pyruvate loss...

Catabolism of carbohydrates - stages 3-4: ◦Specifically related to mitochondria Catabolism of carbohydrates - end of stage 2: ◦Pyruvate is first converted to acetyl CoA by the enzyme pyruvate dehydrogenase (PDH) - regulated allosterically ◦The reaction is irreversible (pyruvate losses one C-atom) ◦The reaction is sensitive to the energy status of the cell ◦Deficiencies of the PDH: (X linked dominant disorder) leading to lactic acidemia - Leigh’s disease (necrotising encephalopathy). Stage 3: Overview: ◦Mitochondrial pathway ◦A single pathway - tricarboxylic acid (TCA) cycle also known as Krebs cycle ◦Oxidative carriers (requires NAD+, FAD) ◦Some energy (as ATP) produced directly ◦Acetylene (Ch3CO-) converted to 2 CO2 ◦Also produces precursors for biosynthesis Catabolism of carbohydrates - stage 3: ◦Tricarboxylic acid cycle: ‣ It is an oxidative pathway that occurs in mitochondria ‣ Requires NAD+, FAD and oxaloacetate ‣ The main function of the pathway is to break the C-C bond in acetate (as acetyl CoA) and oxidise the C-atoms to CO2, which is released  ‣ The H+ and e- removed from acetate are transferred to NAD+ and FAD (NADH and FADH2 produced) ‣ Requires oxygen ‣ Production of ATP and GTP (energy) ‣ Some reactions are irreversible e.g. the reaction to turn isocitric acid into alpha- ketoglutaric acid ‣ Strategy: to produce intermediates (anabolic function) C4-C5: biosynthesis of non-essential amino acids C4: biosynthesis of harm and glucose C6: biosynthesis of fatty acids ‣ Regulation: ATP utilisation (ATP/ADP ratio - NADH/NAD+ ratio) ◦High ADP is a low-energy signal ◦High NADH is a high-energy signal Stage 4 - overview: ◦Mitochondrial process ◦Electron transport and ATP synthesis ◦NADH and FAD2H (coming from TCA cycle) are re-oxidised ◦02 required (reduced to H2O) ◦Large amounts of energy (ATP) produced Catabolism of carbohydrates - stage 4:  Oxidative phosphorylation (OXPHOS): ◦Converts chemical energy (from nutrients) into ATP ◦Energy conserved in reduced carriers (NADH and FADH2) is used to synthesise ATP awarded ◦Two processes, which cannot happen without the other: ‣ Electron transport ‣ ATP synthesis ◦Occurs inside the mitochondria ‣ Complexes are present in the invaginations of the inner membrane of the mitochondria Catabolism of carbohydrates - stage 4: ◦Electron transport: transfer of electrons to molecular oxygen mediated by four specialised complexes (I-IV) ◦Electrons come from NADH and FADH2 shuttled to the intermembrane space. ◦Proton translocation results in “proton-motive force’ also referred to as electro-chemical potential ◦Requires oxygen: reduced to water at complex IV ‣ ATP synthesis: energy from proton-motive force. H+ re-enter the mitochondrial matrix via ATP synthase complex (V) ‣ These two processes are coupled ◦Regulation of OXPHOS: ‣ Normally oxidative phosphorylation and electron transport are tightly coupled ‣ Both regulated by mitochondrial ATP ‣ High ATP = Low ADP ‣ When ADP is low: No substrate for ATP synthase Inward flow of H+ stops Concentration of H+ in the intermitochondrial space increases Prevents further H+ pumping - stops electron transport ‣ Reverses with low ATP  Clinical relevance: stages 3-4: ◦Mitochondrial dysfunction: ‣ Loss of efficiency in the electron transport chain and reductions in the synthesis of ATP ‣ Linked to most human conditions in highly-energetic tissues. For example, the brain (neurodegeneration etc) Mitochondria DNA mutations: abnormal components of the respiratory chain Uncouplers and inhibitors: ◦Uncoupling agents (UCP 1-5): important for heat production (adipose tissue and skeletal muscle) ◦Inhibitors: inhibit transport of electrons (poisons) - no ATP and no hear ◦Patient safety - patients who have been poisoned with uncoupling agents or agents that inhibit the electron transport chain must be treated very rapidly to avoid death. ◦Cyanide inhibits complex 4 of the electron transport chain. Cyanide can also affect glycolysis. Lipids: therefore ◦Generally insoluble in water (hydrophobic) but are soluble in organic solvents ◦Most only contain C, H and O (phospholipids also contain P and N) ◦More reduced than carbohydrates (i.e. they contain less O and more H per C-atom) Lipids - triacylglycerol: ◦Triacylglycerols are the major dietary and storage lipids in the body ◦They consist of three fatty acids (usually long chain where n=16) esterified to glycerol: ◦Triacylglycerol is hydrophobic and are stored in an anhydrous form in adipose tissue  ◦Store of field molecules (fatty acids and glycerol) for: prolonged aerobic exercise, stress situations such as starvation and during pregnancy ◦Storage is under hormonal control being promoted by insulin and reduced by glucagon, adrenaline, cortisol (a glucocorticoid), growth hormone and thyroxine Catabolism of triacylglycerol - stages 1-4: Catabolism of triacylglycerol - stage 1: ◦GI tract (extracellular) (1) Breakdown and (2) Absorption ◦(1) Breakdown: triacylglycerol (butter, ghee, margarine, vegetable oils). Hydrolysed by pancreatic lipase in the small intestine to release glycerol and fatty acids ◦Requires bile salts and a protein factor called co-lipase ◦(2) Absorption: glycerol and fatty acids imported across the intestinal mucosa ◦Once across, the triglycerides are re-synthesised ◦These triglycerides are packaged along with cholesterol molecules in phospholipid vesicles called chylomicrons (which are rich in triacylglycerols) and transported to the liver or adipose tissue. Catabolism of triacylglycerol - stage 2:  ◦Glycerol is metabolised in the liver ◦Requires ATP ◦Glycerol phosphate can be used in the synthesis of triacylglycerol ◦Or enter glucose metabolism (glycolysis) - glycolysis yield pyruvate ◦Fatty acids (FA) are oxidised by beta oxidation into acetyl CoA, which is used by the Krebs cycle (stage 3) ◦Occurs in the mitochondria. ◦Steps: ‣ FA activation: linking to CoA ‣ Transport into mitochondria: social transport mediated by carnitine ‣ Beta oxidation: sequence of reactions (removes 2 carbon units) - no ATP directly - NADH and FADH2 produced Carbon atoms form acetyl-CoA and join the TCA cycle nondenominational Catabolism of fatty acids - stage 3-4: Metabolism of lipids - clinical relevance: ◦Ketone bodies produced in the liver mitochondria from acetyl CoA ◦Acetoacetate and beta-hydroxybutyrate (10 mmol/L) - breath smell of acetone